Acta Derm Venereol 2010; 90: 6–11 MINI-REVIEW A Practical Classification of Childhood Hypopigmentation Disorders Hong Liang TEY National Skin Centre, 1, Mandalay Road, Singapore, Singapore Hypopigmentation disorders in children can be due to a ONSET IN EARLY CHILDHOOD wide variety of congenital and acquired diseases. A clini- cal approach to hypopigmentation disorders based on In this article, disorders that present in early childhood the typical age of onset and the extent of lesions is propo- describe those disorders that occur up to the first 2 sed. The disorders are categorized into onset in early and years of life. Most of these disorders present at birth later childhood, and in each category they are subdivi- or during infancy and have a genetic basis. Clinically, ded into localized and generalized pigmentary disorders. these disorders can be divided into those characterized Clinical findings, comprising the sites of involvement, by generalized hypopigmentation and those causing degree of pigment loss, and associated morphological fin- localized disease. dings, are used to distinguish the disorders further. This classification provides a systematic approach to a clinical Generalized hypopigmentary disorders condition in which the causes are heterogeneous and his- Disorders with generalized diffuse pigmentary dilution tological examination of the skin is rarely diagnostic. Key are usually due to mutations of genes responsible for words: approach; childhood; pediatric; hypopigmentation; the production of melanin or the processing of melano- hypopigmented. somes, and hypopigmentation of the skin and hair is (Accepted October 26, 2009.) present. During embryogenesis, progenitor melanob- lasts migrate between mesodermal and ectodermal lay- Acta Derm Venereol 2010; 90: 6–11. ers to reach their final destinations in the epidermis and hair follicular bulbs, as well as the inner ear cochlea, Hong Liang Tey, National Skin Centre, 1, Mandalay Road, choroids, ciliary body, and iris (1). Therefore, the eyes, Singapore 308205, Singapore. E-mail: teyhongliang111@ in addition to the skin and hair, can exhibit pigmentary yahoo.com dilution. In a group of generalized hypopigmentary dis- orders, hypopigmentation involves the eyes in addition to the skin and hair, and this group has been typified as The colour of the skin is mainly due to melanin and blood oculocutaneous albinism (Fig. 1). but can be altered in non-physiological conditions such as Oculocutaneous albinism (OCA) is the most common carotenemia, drug intake, jaundice and chronic renal fai- type of pigmentary dilutional disorder, of which type 2 lure. Hypopigmentation refers to any form of decreased comprises the majority of the cases. In OCA type 1A, in pigmentation, whereas hypomelanosis refers specifically which there is complete absence of tyrosinase activity, to a decrease in melanin content. Depigmentation, in there is permanent and complete absence of pigment from contrast to hypopigmentation, describes the almost total birth. In OCA types 1B, 2, 3, and 4, however, pigment loss of pigmentation, resulting in a whitish appearance production may increase over time. In these latter types that comes from the underlying dermis. of OCA and including Hermansky–Pudlak and Chediak– Hypopigmentation disorders can generally be cate- Higashi syndromes, the pigmentary dilution may be gorized based on their aetiologies, age of onset, and subtle, and comparison with family members will be extent of involvement. In early childhood, many of helpful. This is especially so in fair-skinned races. these disorders have a genetic origin and present with Common to all types of OCA, there is reduced visual generalized pigmentary dilution. In later childhood, acuity and ocular nystagmus (2) and these distinguish many of these diseases are acquired and cause localized OCA from other forms of congenital hypopigmentation. hypopigmentation. Other clinical features can aid in The ocular abnormalities are due to misrouting of the the further differentiation of these disorders, such as optic nerve and this may result from deficiency of tyro- the sites of involvement, degree of pigment loss, and sinase. Tyrosine hydroxylase, in particular, is important associated morphological signs. In the clinical approach in the proper routing of retinal projections at the optic to be presented here, the disorders are categorized pri- chiasm during development (3). Infants who are unable marily according to the typical age of onset into early to fixate or have nystagmus should be sent for a thorough and later childhood. ocular examination as early intervention is crucial for Acta Derm Venereol 90 © 2010 The Authors. doi: 10.2340/00015555-0794 Journal Compilation © 2010 Acta Dermato-Venereologica. ISSN 0001-5555 Childhood hypopigmentation 7 Onset in early childhood melanolysosomal disease, is characterized Generalised hypopigmentation by silvery hair, mild hypopigmentation, Eyes, skin and severe central nervous system dysfun- Skin and hair and hair ction (6). Its molecular basis is currently not known. Oculocutaneous Inborn errors Nutritional Genodermatoses albinism of metabolism deficiencies Menkes syndrome is an X-linked re- cessive multi-systemic disorder due to Defects in Defects in Unknown Phenylketonuria Neurologic melanin packaging of Copper inappropriate intracellular copper storage. mechanism defects production melanosomes It is typified by hair shaft abnormalities, Homocysteinuria Griscelli and Hermansky- Cross Elejalde OCA 1-4 Pudlak syndrome of which pili torti is the most common. syndromes Selenium syndrome Histidinaemia Pigmentary abnormalities consist of Menkes Prader-Willi & Chediak-Higashi syndrome lightly pigmented hair and generalized Angelman syndrome syndromes or localized hypopigmentation. Progres- Skeletal defects sive central nervous system deterioration occurs and results in death by 3 years of EEC syndrome age (7). Fig. 1. Generalized hypopigmentation with early onset. Pigmentary dilution and skeletal de- fects occur in Ectrodactyly-Ectodermal dysplasia-Cleft lip/palate (EEC) syn- visual development. In addition, hypopigmented babies drome. The “lobster-claw” deformities of the hands should undergo a systemic evaluation to exclude other and feet and cleft lip and palate enable the syndrome rarer disorders. For example, the presence of mental retar- to be recognized easily. The cutaneous features consist dation suggests Angelman and Prader–Willi syndromes, of diffuse hypopigmentation and dryness of the skin an obese baby may have Prader–Willi syndrome, bleeding and hair (8). diatheses may be a sign of Hermansky–Pudlak syndrome, Loss of hair and skin pigmentation due to selenium immune deficiency points to Chediak–Higashi syndrome, deficiency has been described in children receiving and structural ocular and neurological abnormalities sug- long-term total parenteral nutrition, and repigmentation gest Cross syndrome. occurred after selenium supplementation (9). Hypopig- Impairment of melanin synthesis occurs in certain mentation of the skin and hair has also been described diseases of inborn errors of metabolism, such as phenyl­­- in severely malnourished infants, and this was attributed ketonuria, homocystinuria and histidinaemia, which are to copper deficiency because tyrosinase is a copper- due to the absence or defect in phenylalanine hydroxy- dependent enzyme. However, as multiple nutritional lase, cystathionine synthetase, and histidase, respecti- deficiencies tend to co-exist, the pathogenesis was dif- vely. These three disorders are transmitted in an auto- ficult to confirm (10). somal recessive manner and are associated with mental In all of the disorders outlined in Fig. 1, the epidermis retardation and other systemic dysfunction. generally contains normal numbers of melanocytes and Some genetic disorders result in pigmentary dilution histology of the skin is not helpful in differentiating of the skin and hair, but spare the eyes. The patients these conditions. The pathophysiological defect of should be screened for systemic abnormalities and if hypopigmentation lies either in melanin biosynthesis neurological defects are present, the differential di- or melanosome formation and trafficking. Disorder of agnoses will include Griscelli, Elejalde and Menkes melanin biosynthesis can be due to tyrosinase defects syndromes. Griscelli and Elejalde syndromes are rare, (occurring in OCA types 1 and 3 and copper deficiency) autosomal recessive disorders with abnormalities in the or melanosomal dysfunction (occurring in OCA types transport of lysosome-related organelles, which include 2 to 4). Abnormalities in the formation, transport, and melanosomes, platelet-dense bodies and lymphocyte transfer of melanosomes occur in Hermansky–Pudlak, lytic granules (4). Besides cutaneous pigmentatory dilu- Chediak–Higashi, and Griscelli syndromes. tion, the consequence of disrupted melanosome transfer is silver discoloration of the hair, which can be seen to contain multiple clumps of melanin under light micro- Localized hypopigmentary disorders scopy. In fact, Griscelli, Elejalde and Chediak–Higashi Localized hypopigmentation presenting in early child- syndromes have been termed “silvery hair syndromes” hood can be due to genetic or acquired causes. These (5). Apart from pigmentary dilution and neurological disorders can clinically be categorized based on whether abnormalities, Griscelli syndrome is also characterized the lesions are depigmented or hypopigmented (Fig. 2). by immunological impairment.